The overall objective of this Program Project is to define the role of sex hormones (androgens, estrogens and progestins) in regulating the innate immune system as it functions systemically and at mucosal surfaces. We will define the mechanisms whereby sex hormones influence phenotype, innate function, and communication between the innate and adaptive immune systems. Our intent is to use peripheral blood cells from men and women, cell lines, and immune cells and tissues from the FRT to define the role of sex hormone and pathogenic challenge at the cellular and molecular level. We postulate that innate immunity (epithelial cells, neutrophils, macrophages and NK cells) is under male and female sex hormone control and that, in addition to conferring protection, each of these cells is capable of initiating an adaptive immune response. Support for four Projects will be provided by three Cores: Administrative, Tissue, and Technical Support. Project 1 will define how sex hormones influence human FRT epithelial cells to initiate and modulate innate immunity throughout the FRT. We will test the hypothesis that sex hormones regulate innate function and define the relationship between epithelial anti-bacterial response and specific Toll-like receptors (TLRs) in response to microbial components (pathogen-associated molecular pattern molecules [PAMP]) as well as define the interactions between innate and adaptive immunity. Project 2 will define the effect of gender and sex hormones on polymorphonuclear neutrophil (PMN) function. Our findings that PMN produce interferon (IFN)gamma and that estradiol down-regulates PMN oxidative burst provides a foundation for studies to test the hypothesis that sex hormones modulate PMN trans-endothelial migration, effector cell function and susceptibility to apoptosis and, thus, innate immunity. Project 3 will focus on the role of sex hormones on the differentiation of monocytes into macrophages (and dendritic cells [DCs]), on immune cell function and the capacity of these cells to initiate adaptive immune responses. These studies will test the hypothesis that sex hormones influence macrophage/DC responses to PAMP and influence microbe-dependent conversion of these cells from an anti- to pro-inflammatory phenotype. Project 4 will test the hypothesis that peripheral NK cells from men and women and NK cells in the FRT are differentially regulated by androgens and estrogens. These studies will examine the mechanism(s) by which sex hormones regulate NK phenotype and effector function as well as enhance and/or lower NK cytolytic activity, cytokine production, and the recruitment of NK cells to the FRT. Overall, these studies may increase our limited understanding of the role of sex hormones in regulating immune protection and should provide the basis of knowledge essential for understanding the role of hormones in autoimmune diseases, the prevention and management of sexually transmitted diseases, and insight into the heterosexual transmission HIV-1.